We are proposing a program of research to identify in mice genetic varients with altered regulatory mechanisms and use these variants together with others previously discovered, to study at the molecular level mammalian regulatory mechanisms controlling (1) rates of enzyme synthesis and degradation; (2) incorporation of completed enzyme molecules into cell organelles: and (3) the timing of enzyme synthesis during development. Because many of these studies are centered on the group of acid hydrolases, we also hope to develop models of lysosomal biogenesis and regulation. The primary purpose of this program is to combine a genetic with a biochemical approach to examine protein regulation in mouse cells and thereby develop general models of mammalian regulation. However, these studies should also aid in the understanding of particular human genetic disorders showing polygenic inheritance or involving lysosomal hydrolases. BIBLIOGRAPHIC REFERENCES: Brandt, E. J., Elliott, R. E. and Swank, R. T., Defective lysosomal enzyme secretion in kidneys of Chediak-Higashi (beige) mice. J. Cell Biol. 67: 774-788 (1975). Brandt, E. J. and Swank, R. T., The Chediak-Higashi (Beige) mutation in two mouse strains: allelism and similarity in lysosomal dysfunction. Am. J. Pathol. 82, March 1976.